Attenuated respiratory syncytial virus vaccine compositions

Abstract

The present invention provides vaccine compositions of attenuated respiratory syncytial virus (RSV). More particularly, the attenuated virus may be a derivative of RSV which has been incompletely attenuated by cold-passage or introduction of mutations which produce virus having a temperature sensitive (ts) or cold adapted (ca) phenotype. The invention also provides methods for stimulating the immune system of an individual to induce protection against respiratory syncytial virus by administration of attenuated RSV. The invention also provides pure cultures of attenuated RS virus, wherein the virus has been more completely attenuated by the further derivatization of previously identified incompletely attenuated ts or cp mutants.

What is claimed is: 
     
       1. An immunogenic composition comprising, in a physiologically acceptable carrier, at least one attenuated respiratory syncytial virus having at least two attenuating mutations, which is a temperature-sensitive mutant of a host range-restricted cold-passaged respiratory syncytial virus. 
     
     
       2. The immunogenic composition according to claim 1, which induces a respiratory syncytial virus special immune response in seropositive individuals having a titer of respiratory syncytial virus neutralizing antibody to wild type respiratory syncytial virus of at least 1:20. 
     
     
       3. The immunogenic composition according to claim 2, wherein the said seropositive individuals for respiratory syncytial virus neutralizing antibody are infants possessing transplacentally acquired respiratory syncytial virus neutralizing antibodies. 
     
     
       4. The immunogenic composition according to claim 1, which further comprises an adjuvant to enhance the immune response. 
     
     
       5. An immunogenic composition according to claim 1, wherein the attenuated virus has been further attenuated by introducing one or more additional mutations which render the virus more temperature sensitive or unable to produce wild type size plaques on tissue culture. 
     
     
       6. The immunogenic composition of claim 1, wherein the attenuated virus is at least one selected from subgroup A or subgroup B. 
     
     
       7. The immunogenic composition of claim 1, wherein the attenuated virus is of a strain of subgroup A. 
     
     
       8. The immunogenic composition of claim 1, wherein the attenuated virus is of a strain of subgroup B. 
     
     
       9. The immunogenic composition of claim 1, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404, 248/955;   (ii) cpts RSV 530, 530/1009, 530/1030; and   iii RSV B-1 cp52/2B5, RSV B-1 cp23.   
     
     
       10. The immunogenic composition of claim 1, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404, 248/955;   (ii) cpts RSV 530, 530/1009; and   (iii) RSV B-1 cp52/2B5, RSV B-1 cp23.   
     
     
       11. The immunogenic composition of claim 1, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404;   (ii) cpts RSV 530; 530/1009; and   (iii) RSV B-1 cp52/2B5.   
     
     
       12. The immunogenic composition of claim 1, formulated in a dose of 10 3  to 10 6  plaque forming units of attenuated virus. 
     
     
       13. A method for stimulating the respiratory syncytial virus specific immune response, which comprises administering to an individual an immunologically sufficient amount of at least one attenuated virus which is a temperature-sensitive mutant of a host range-restricted cold-passaged respiratory syncytial virus in a physiologically acceptable carrier. 
     
     
       14. The method of claim 13, wherein the attenutated virus has been further attenuated by introducing two or more mutations which render the virus more temperature sensitive or unable to produce wild-type size plaques on tissue culture. 
     
     
       15. The method of claim 13, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404, 248/955   (ii) cpts RSV 530, 530/1009, 530/1030; and   (iii) RSV B-1 cp52/2B5, RSV B-1 cp23.   
     
     
       16. The method of claim 13, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404, 248/955;   (ii) cpts RSV 530, 530/1009; and   (iii) RSV B-1 cp52/2B5, RSV B-1 cp23.   
     
     
       17. The method of claim 13, wherein the attenuated respiratory syncytial virus is selected from the group: (i) cpts RSV 248, 248/404;   (ii) cpts RSV 530; 530/1009; and   (iii) RSV B-1 cp52/2B5.   
     
     
       18. The method of claim 13, wherein the attenuated virus is administered to the individual in an amount of 10 3  to 10 6  plaque forming units. 
     
     
       19. The method of claim 13, wherein the attenuated virus is administered to the upper respiratory tract of said individual. 
     
     
       20. The method of claim 19, wherein the attenuated virus is administered to the nasopharynx. 
     
     
       21. The method of claim 19, wherein the attenuated virus is administered by spray, droplet, or aerosol. 
     
     
       22. The method of claim 13, wherein the attenuated virus is administered to an individual having a titer of neutralizing antibodies to wild-type RSV of less than 1:20. 
     
     
       23. The method of claim 13, wherein the attenuated virus is administered to an individual having a titer of neutralizing antibodies to wild-type RSV of at least 1:20. 
     
     
       24. The immunogenic composition of claim 1, wherein the attenuated respiratory syncytial virus is selected from: (i) cpts RSV 248/404;   (ii) cpts RSV 530/1009; or   (iii) RSV B-1 cp52/2B5.   
     
     
       25. The method of claim 13, wherein the attenuated respiratory syncytial virus is selected from: (i) cpts RSV 248/404;   (ii) cpts RSV 530/1009; or   (iii) RSV B-1 cp52/2B5.   
     
     
       26. The immunogenic composition according to claim 1, which induces a respiratory syncytial virus special immune response in a seronegative individual having a titer of respiratory syncytial virus neutralizing antibody of less than 1:20.